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Article ; Online: Monogenic diabetes in adults: what are the new developments?

Owen, Katharine R

Current opinion in genetics & development

2018 Volume 50, Page(s) 103–110

Abstract: Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic causes of beta-cell dysfunction and diabetes arising in children and young adults. Making an accurate diagnosis of MODY is important for establishing the correct management. ...

Abstract	Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic causes of beta-cell dysfunction and diabetes arising in children and young adults. Making an accurate diagnosis of MODY is important for establishing the correct management. Recent advances in our understanding of human sequence variation, through data collated in resources such as the Exome Aggregation Consortium have refined guidelines for assessment of rare genetic variants. This will allow a more precise aetiological diagnosis in childhood and young adult diabetes. No major new monogenic causes of diabetes outside the neonatal period have been identified in recent years, but the allelic spectrum of disease phenotype associated with known genes continues to expand. Improving uptake of genetic testing by defining who should be tested is an area of active research. A population based study found that 6.5% of children who have negative beta-cell antibodies at diagnosis have rare functional variants in MODY genes. Defining the high risk groups in adults with diabetes is more difficult, but online decision aids will assist clinicians in selecting who to refer for testing.
MeSH term(s)	Adolescent ; Child ; Child, Preschool ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/pathology ; Exome/genetics ; Genetic Testing ; Humans ; Insulin-Secreting Cells/pathology ; Mutation ; Phenotype ; Young Adult
Language	English
Publishing date	2018-05-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2018.04.006
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Article ; Online: Treating young adults with type 2 diabetes or monogenic diabetes.

Owen, Katharine R

Best practice & research. Clinical endocrinology & metabolism

2016 Volume 30, Issue 3, Page(s) 455–467

Abstract: It is increasingly recognised that diabetes in young adults has a wide differential diagnosis. There are many monogenic causes, including monogenic beta-cell dysfunction, mitochondrial diabetes and severe insulin resistance. Type 2 diabetes in the young ... ...

Abstract	It is increasingly recognised that diabetes in young adults has a wide differential diagnosis. There are many monogenic causes, including monogenic beta-cell dysfunction, mitochondrial diabetes and severe insulin resistance. Type 2 diabetes in the young is becoming more prevalent, particularly after adolescence. It's important to understand the clinical features and diagnostic tools available to classify the different forms of young adult diabetes. Classic type 1 diabetes is characterised by positive β-cell antibodies and absence of endogenous insulin secretion. Young type 2 diabetes is accompanied by metabolic syndrome with obesity, hypertension and dyslipidaemia. Monogenic β-cell dysfunction is characterised by non-autoimmune, C-peptide positive diabetes with a strong family history, while mitochondrial diabetes features deafness and other neurological involvement. Severe insulin resistance involves a young-onset metabolic syndrome often with a disproportionately low BMI. A suspected diagnosis of monogenic diabetes is confirmed with genetic testing, which is widely available in specialist centres across the world. Treatment of young adult diabetes is similarly diverse. Mutations in the transcription factors HNF1A and HNF4A and in the β-cell potassium ATP channel components cause diabetes which responds to low dose and high dose sulfonylurea agents, respectively, while glucokinase mutations require no treatment. Monogenic insulin resistance and young-onset type 2 diabetes are both challenging to treat, but first line management involves insulin sensitisers and aggressive management of cardiovascular risk. Outcomes are poor in young-onset type 2 diabetes compared to both older onset type 2 and type 1 diabetes diagnosed at a similar age. The evidence base for treatments in monogenic and young-onset type 2 diabetes relies on studies of moderate quality at best and largely on extrapolation from work conducted in older type 2 diabetes subjects. Better quality, larger studies, particularly of newer agents would improve treatment prospects for young adults with diabetes.
MeSH term(s)	Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/genetics ; Glucokinase/genetics ; Hepatocyte Nuclear Factor 1-alpha/genetics ; Hepatocyte Nuclear Factor 4/genetics ; Humans ; Hypoglycemic Agents/therapeutic use ; KATP Channels/genetics ; Mutation ; Precision Medicine
Chemical Substances	HNF1A protein, human ; HNF4A protein, human ; Hepatocyte Nuclear Factor 1-alpha ; Hepatocyte Nuclear Factor 4 ; Hypoglycemic Agents ; KATP Channels ; Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2016-06
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2052339-7
ISSN	1878-1594 ; 1532-1908 ; 1521-690X
ISSN (online)	1878-1594 ; 1532-1908
ISSN	1521-690X
DOI	10.1016/j.beem.2016.05.002
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Article ; Online: Genetics of Monogenic Diabetes: Present Clinical Challenges.

Misra, Shivani / Owen, Katharine R

Current diabetes reports

2018 Volume 18, Issue 12, Page(s) 141

Abstract: Purpose of review: Monogenic forms of diabetes have specific treatments that differ from the standard care provided for type 1 and type 2 diabetes, making the appropriate diagnosis essential. In this review, we discuss current clinical challenges that ... ...

Abstract	Purpose of review: Monogenic forms of diabetes have specific treatments that differ from the standard care provided for type 1 and type 2 diabetes, making the appropriate diagnosis essential. In this review, we discuss current clinical challenges that remain, including improving case-finding strategies, particularly those that have transethnic applicability, and understanding the interpretation of genetic variants as pathogenic, with clinically meaningful impacts. Recent findings: Biomarker approaches to the stratification for genetic testing now appear to be most effective in identifying cases of monogenic diabetes, and use of genetic risk scores may also prove useful. However, applicability in all ethnic groups is lacking. Challenges remain in the classification of genes as diabetes-causing and the interpretation of genetic variants at the clinical interface. Since the discovery that genetic defects can cause neonatal or young-onset diabetes, multiple causal genes have been identified and there have been many advances in strategies to detect genetic forms of diabetes and their treatments. Approaches learnt from monogenic diabetes are now being translated to polygenic diabetes.
MeSH term(s)	Biomarkers/metabolism ; Diabetes Mellitus/genetics ; Ethnic Groups/genetics ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Mutation/genetics
Chemical Substances	Biomarkers
Language	English
Publishing date	2018-10-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2065167-3
ISSN	1539-0829 ; 1534-4827
ISSN (online)	1539-0829
ISSN	1534-4827
DOI	10.1007/s11892-018-1111-4
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Article: Monogenic diabetes: old and new approaches to diagnosis.

Owen, Katharine R

Clinical medicine (London, England)

2013 Volume 13, Issue 3, Page(s) 278–281

Abstract: Up to 5% of young adults diagnosed with diabetes have a monogenic aetiology, the most common of which is maturity-onset diabetes of the young (MODY). A definitive molecular diagnosis is important, as this affects treatment, prognosis and family screening. ...

Abstract	Up to 5% of young adults diagnosed with diabetes have a monogenic aetiology, the most common of which is maturity-onset diabetes of the young (MODY). A definitive molecular diagnosis is important, as this affects treatment, prognosis and family screening. Currently, however, rates of diagnosis are low due to a combination of lack of awareness of the benefits of making the diagnosis and the challenges of differentiating patients with MODY from those with common forms of diabetes. This article aims to introduce general physicians to the characteristics of monogenic diabetes and the clinical features that can be used to diagnose patients. Recently, genomewide association studies have resulted in the identification of C-reactive protein and glycan profile as specific biomarkers for the most common MODY subtype due to HNF1A mutations, and the potential translation of these findings are discussed.
MeSH term(s)	Adult ; Algorithms ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Diabetes Mellitus, Type 1/diagnosis ; Diabetes Mellitus, Type 1/genetics ; Diagnosis, Differential ; Glucokinase/blood ; Hepatocyte Nuclear Factor 1-alpha/blood ; Hepatocyte Nuclear Factor 1-beta/blood ; Humans ; Mutation ; Prognosis
Chemical Substances	Biomarkers ; HNF1A protein, human ; Hepatocyte Nuclear Factor 1-alpha ; Hepatocyte Nuclear Factor 1-beta (138674-15-4) ; C-Reactive Protein (9007-41-4) ; Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2013-06-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2048646-7
ISSN	1473-4893 ; 1470-2118
ISSN (online)	1473-4893
ISSN	1470-2118
DOI	10.7861/clinmedicine.13-3-278
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Article ; Online: Transdermal Blood Sampling for C-Peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes.

Besser, Rachel E J / Long, Anna E / Owen, Katharine R / Law, Rebecca / Birks, Jacqueline S / Pearce, Olivia / Williams, Claire L / Scudder, Claire L / McDonald, Timothy J / Todd, John A

Diabetes care

2023 Volume 47, Issue 2, Page(s) 239–245

Abstract: Objective: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative.: Research design ... ...

Abstract	Objective: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. Research design and methods: Ninety-one individuals (71 with type 1 diabetes, 20 control; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1-17.1], diabetes duration 4.0 years [1.5-7.7]; control individuals: 42.2 years [38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire. Results: Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40-50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) <35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] - TCB ln[C-peptide] = 0.008, 95% CI [-0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided). Conclusions: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment.
MeSH term(s)	Adult ; Child ; Humans ; Aged ; Diabetes Mellitus, Type 1 ; C-Peptide ; Autoantibodies ; Blood Specimen Collection ; Biomarkers ; Glutamate Decarboxylase
Chemical Substances	C-Peptide ; Autoantibodies ; Biomarkers ; Glutamate Decarboxylase (EC 4.1.1.15)
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	441231-x
ISSN	1935-5548 ; 0149-5992
ISSN (online)	1935-5548
ISSN	0149-5992
DOI	10.2337/dc23-1379
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Article: A Systematic Review of the use of Precision Diagnostics in Monogenic Diabetes.

Murphy, Rinki / Colclough, Kevin / Pollin, Toni I / Ikle, Jennifer M / Svalastoga, Pernille / Maloney, Kristin A / Saint-Martin, Cécile / Molnes, Janne / Misra, Shivani / Aukrust, Ingvild / de Franco, aiElisa / Flanagan, Sarah E / Njølstad, Pål R / Billings, Liana K / Owen, Katharine R / Gloyn, Anna L

medRxiv : the preprint server for health sciences

2023

Abstract: Monogenic forms of diabetes present opportunities for precision medicine as identification of the underlying genetic cause has implications for treatment and prognosis. However, genetic testing remains inconsistent across countries and health providers, ... ...

Abstract	Monogenic forms of diabetes present opportunities for precision medicine as identification of the underlying genetic cause has implications for treatment and prognosis. However, genetic testing remains inconsistent across countries and health providers, often resulting in both missed diagnosis and misclassification of diabetes type. One of the barriers to deploying genetic testing is uncertainty over whom to test as the clinical features for monogenic diabetes overlap with those for both type 1 and type 2 diabetes. In this review, we perform a systematic evaluation of the evidence for the clinical and biochemical criteria used to guide selection of individuals with diabetes for genetic testing and review the evidence for the optimal methods for variant detection in genes involved in monogenic diabetes. In parallel we revisit the current clinical guidelines for genetic testing for monogenic diabetes and provide expert opinion on the interpretation and reporting of genetic tests. We provide a series of recommendations for the field informed by our systematic review, synthesizing evidence, and expert opinion. Finally, we identify major challenges for the field and highlight areas for future research and investment to support wider implementation of precision diagnostics for monogenic diabetes.
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.15.23288269
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Article ; Online: The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.

Murphy, Rinki / Colclough, Kevin / Pollin, Toni I / Ikle, Jennifer M / Svalastoga, Pernille / Maloney, Kristin A / Saint-Martin, Cécile / Molnes, Janne / Misra, Shivani / Aukrust, Ingvild / de Franco, Elisa / Flanagan, Sarah E / Njølstad, Pål R / Billings, Liana K / Owen, Katharine R / Gloyn, Anna L

Communications medicine

2023 Volume 3, Issue 1, Page(s) 136

Abstract: Background: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized ... ...

Abstract	Background: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field. Methods: Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice. Results: There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted. Conclusions: We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.
Language	English
Publishing date	2023-10-05
Publishing country	England
Document type	Journal Article
ISSN	2730-664X
ISSN (online)	2730-664X
DOI	10.1038/s43856-023-00369-8
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Article ; Online: Glucokinase MODY and implications for treatment goals of common forms of diabetes.

Ajjan, Ramzi A / Owen, Katharine R

Current diabetes reports

2014 Volume 14, Issue 12, Page(s) 559

Abstract: Treatment goals in diabetes concentrate on reducing the risk of vascular complications, largely through setting targets for glycated haemoglobin (HbA1c). These targets are based on epidemiological studies of complication development, but so far have not ... ...

Abstract	Treatment goals in diabetes concentrate on reducing the risk of vascular complications, largely through setting targets for glycated haemoglobin (HbA1c). These targets are based on epidemiological studies of complication development, but so far have not adequately addressed the adverse effects associated with lowering HbA1c towards the normal range. Glucokinase (GCK) mutations cause a monogenic form of hyperglycaemia (GCK-MODY) characterised by fasting hyperglycaemia with low postprandial glucose excursions and a marginally elevated HbA1c. Minimal levels of vascular complications (comparable with nondiabetic individuals) are observed in GCK-MODY, leading to the hypothesis that GCK-MODY may represent a useful paradigm for assessing treatment goals in all forms of diabetes. In this review, we discuss the evidence behind this concept, suggest ways of translating this hypothesis into clinical practice and address some of the caveats of such an approach.
MeSH term(s)	Diabetes Mellitus, Type 2/enzymology ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/mortality ; Diabetes Mellitus, Type 2/therapy ; Glucokinase/genetics ; Goals ; Humans ; Models, Biological ; Molecular Targeted Therapy
Chemical Substances	Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2014-10-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2065167-3
ISSN	1539-0829 ; 1534-4827
ISSN (online)	1539-0829
ISSN	1534-4827
DOI	10.1007/s11892-014-0559-0
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Article ; Online: First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes.

Van Rampelbergh, Jean / Achenbach, Peter / Leslie, Richard David / Ali, Mohammad Alhadj / Dayan, Colin / Keymeulen, Bart / Owen, Katharine R / Kindermans, Martin / Parmentier, Frédéric / Carlier, Vincent / Ahangarani, Roxana R / Gebruers, Evelien / Bovy, Nicolas / Vanderelst, Luc / Van Mechelen, Marcelle / Vandepapelière, Pierre / Boitard, Christian

BMC medicine

2023 Volume 21, Issue 1, Page(s) 190

Abstract: Background: Type 1 diabetes (T1D) is a CD4: Methods: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were ... ...

Abstract	Background: Type 1 diabetes (T1D) is a CD4 Methods: This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 μg for priming followed by three further administrations of 25/75/225 μg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients. Results: Treatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change - 0.108, - 0.041, - 0.040, and - 0.012, respectively), suggesting no disease progression. Conclusions: Promising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. Trial registration: IMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018-003728-35.
MeSH term(s)	Adult ; Humans ; Diabetes Mellitus, Type 1/drug therapy ; CD8-Positive T-Lymphocytes ; Immunotherapy ; C-Peptide ; Autoimmunity ; Disease Progression
Chemical Substances	C-Peptide
Language	English
Publishing date	2023-05-24
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2131669-7
ISSN	1741-7015 ; 1741-7015
ISSN (online)	1741-7015
ISSN	1741-7015
DOI	10.1186/s12916-023-02900-z
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Article ; Online: Fucosylated AGP glycopeptides as biomarkers of HNF1A-Maturity onset diabetes of the young.

Tijardović, Marko / Štambuk, Tamara / Juszczak, Agata / Keser, Toma / Gasperikova, Daniela / Novokmet, Mislav / Tjora, Erling / Pape Medvidović, Edita / Stanik, Juraj / Rasmus Njølstad, Pål / Lauc, Gordan / Owen, Katharine R / Gornik, Olga

Diabetes research and clinical practice

2022 Volume 185, Page(s) 109226

Abstract: Aims: We previously demonstrated that antennary fucosylated N-glycans on plasma proteins are regulated by HNF1A and can identify cases of Maturity-Onset Diabetes of the Young caused by HNF1A variants (HNF1A-MODY). Based on literature data, we further ... ...

Abstract	Aims: We previously demonstrated that antennary fucosylated N-glycans on plasma proteins are regulated by HNF1A and can identify cases of Maturity-Onset Diabetes of the Young caused by HNF1A variants (HNF1A-MODY). Based on literature data, we further postulated that N-glycans with best diagnostic value mostly originate from alpha-1-acid glycoprotein (AGP). In this study we analyzed fucosylation of AGP in subjects with HNF1A-MODY and other types of diabetes aiming to evaluate its diagnostic potential. Methods: A recently developed LC-MS method for AGP N-glycopeptide analysis was utilized in two independent cohorts: a) 466 subjects with different diabetes subtypes to test the fucosylation differences, b) 98 selected individuals to test the discriminative potential for pathogenic HNF1A variants. Results: Our results showed significant reduction in AGP fucosylation associated to HNF1A-MODY when compared to other diabetes subtypes. Additionally, ROC curve analysis confirmed significant discriminatory potential of individual fucosylated AGP glycopeptides, where the best performing glycopeptide had an AUC of 0.94 (95% CI 0.90-0.99). Conclusions: A glycopeptide based diagnostic tool would be beneficial for patient stratification by providing information about the functionality of HNF1A. It could assist the interpretation of DNA sequencing results and be a useful addition to the differential diagnostic process.
MeSH term(s)	Biomarkers ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/genetics ; Glycopeptides/genetics ; Hepatocyte Nuclear Factor 1-alpha/genetics ; Hepatocyte Nuclear Factor 1-alpha/metabolism ; Humans ; Mutation ; Polysaccharides/metabolism
Chemical Substances	Biomarkers ; Glycopeptides ; HNF1A protein, human ; Hepatocyte Nuclear Factor 1-alpha ; Polysaccharides
Language	English
Publishing date	2022-02-02
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	632523-3
ISSN	1872-8227 ; 0168-8227
ISSN (online)	1872-8227
ISSN	0168-8227
DOI	10.1016/j.diabres.2022.109226
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